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Montelukast

Class: Leukotriene Modifiers
VA Class: RE109
Chemical Name: [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl cyclopropane acetic acid sodium
Molecular Formula: C35H35ClNNaO3S
CAS Number: 151767-02-1
Brands: Singulair

Medically reviewed by Drugs.com on Dec 21, 2020. Written by ASHP.

Warning

  • Serious neuropsychiatric effects, including suicidal thoughts or behavior, reported in patients receiving montelukast. (See Neuropsychiatric Effects under Cautions.)

  • Discuss benefits and risks of treatment with patients and caregivers; monitor patients receiving montelukast for neuropsychiatric symptoms.

  • Discontinue montelukast if neuropsychiatric symptoms occur and contact a clinician immediately.

  • Benefits of montelukast treatment may not outweigh the risks of neuropsychiatric symptoms, especially for respiratory disease symptoms that may be mild and adequately treated with alternative therapies. Reserve use of the drug for patients with allergic rhinitis who have an inadequate response or intolerance to alternative therapies. In patients with asthma or exercise-induced bronchospasm, consider the benefits and risks of treatment before prescribing montelukast.

Introduction

Antiasthmatic agent; leukotriene modifier. Pharmacologically but not structurally related to zafirlukast.

Uses for Montelukast

Asthma

Prevention and long-term symptomatic management of asthma. Efficacy for this indication demonstrated when the drug was administered in the evening.

Because of the risk of neuropsychiatric effects, consider the benefits and risks of montelukast treatment before prescribing the drug for patients with asthma. (See Neuropsychiatric Effects under Cautions.)

In patients with mild persistent asthma, low-dose orally inhaled corticosteroids considered first-line agents for long-term control. Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), may be used but are less effective than inhaled corticosteroids and are not preferred as initial therapy.

In patients with moderate persistent asthma, low-dose inhaled corticosteroids with a long-acting inhaled β2-agonist bronchodilator (e.g., salmeterol, formoterol) or monotherapy with medium-dose inhaled corticosteroids preferred. However, the National Asthma Education and Prevention Program (NAEPP) recommends that beneficial effects of long-acting inhaled β2-agonists be weighed carefully against increased risk of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents.

Alternative agents, including certain leukotriene modifiers (i.e., montelukast, zafirlukast), can be added to a low dosage of inhaled corticosteroid for treatment of moderate persistent asthma, but these options are less effective. Considerations favoring combination with orally inhaled corticosteroids include intolerance to long-acting β2-adrenergic agonists, marked preference for oral therapy, and demonstration of superior responsiveness to these leukotriene modifiers.

In adults and children ≥5 years of age with severe persistent asthma, NAEPP and the Global Initiative for Asthma (GINA) state that maintenance therapy with inhaled corticosteroids at medium to high dosages and adjunctive therapy with a long-acting inhaled β2-agonist is preferred. Alternatives to a long-acting inhaled β2-agonist in such patients receiving medium-dose inhaled corticosteroids include certain leukotriene modifiers (i.e., montelukast, zafirlukast), but these agents are generally not preferred.

In infants and children ≤4 years of age, NAEPP states that an inhaled corticosteroid at medium or high dosages and adjunctive therapy with either a long-acting inhaled β2-agonist or montelukast is the only preferred treatment.

Maintenance therapy with montelukast may be considered in patients who are unable or unwilling to comply with therapy using inhaled corticosteroids (e.g., young children).

Not recommended for relief of acute bronchospasm; however, may continue therapy during acute asthma exacerbations. (See Acute Asthma under Cautions.)

Exercise-induced Bronchospasm

Prevention of exercise-induced bronchospasm.

Because of the risk of neuropsychiatric effects, consider the benefits and risks of montelukast treatment before prescribing the drug for patients with exercise-induced bronchospasm. (See Neuropsychiatric Effects under Cautions.)

Leukotriene modifiers not included as first-line agents or as alternative agents to orally inhaled β2-adrenergic agonists in current guidelines; addition of montelukast may provide additional measure of control in patients currently maintained on long-term controller therapy.

Manufacturer states that patients who experience exacerbations of asthma after exercise should have a short-acting orally inhaled β2-adrenergic agonist available for rescue. Not established that daily administration of montelukast for chronic treatment of asthma prevents acute episodes of exercise-induced bronchospasm.

Allergic Rhinitis

Symptomatic management of seasonal or perennial allergic rhinitis. Efficacy for this indication demonstrated when the drug was administered in the morning or evening.

Because the benefits of montelukast treatment may not outweigh the risks of neuropsychiatric effects in patients with allergic rhinitis, reserve use of the drug for such patients who have an inadequate response or intolerance to alternative therapies. (See Neuropsychiatric Effects under Cautions.)

Urticaria

Has been used successfully in patients with chronic idiopathic urticaria; beneficial when added to existing therapy.

Montelukast Dosage and Administration

Administration

Oral Administration

Administer at regular intervals (once daily) without regard to meals.

Administer in the evening in patients with asthma with or without coexisting allergic rhinitis.

May individualize time of administration in patients with allergic rhinitis; administer at the same time each day.

Administer ≥2 hours before exercise in patients with exercise-induced bronchospasm; do not take an additional dose within 24 hours of previous dose.

Oral Granules

Generally used in children 12 months to 5 years of age. Do not open packet until ready to use; administer full dose within 15 minutes of opening packet and without regard to meals.

Administer directly in the mouth alone or mix with a teaspoonful (5 mL) of cold or room temperature baby formula, breast milk, or soft food (i.e., applesauce, carrots, rice, ice cream). Granules are not intended to be dissolved in liquid other than baby formula or breast milk prior to administration; however, liquids can be taken after administration of the granules. (See Stability.)

Do not store granules mixed with food for future use; discard any unused portion.

Dosage

Available as montelukast sodium; dosage expressed in terms of montelukast.

Pediatric Patients

Asthma With or Without Allergic Rhinitis
Oral

Children 12–23 months: 4 mg once daily as oral granules.

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.

Children 6–14 years of age: 5 mg once daily as chewable tablets.

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.

Additional dosage not needed for treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.

Exercise-induced Bronchospasm
Prevention
Oral

Children 6–14 years of age: 5 mg as a chewable tablet administered at least 2 hours before exercise.

Adolescents ≥15 years of age: 10 mg as a film-coated tablet administered at least 2 hours before exercise.

Not indicated in those already taking the drug for another indication.

Seasonal Allergic Rhinitis With or Without Asthma
Oral

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.

Children 6–14 years of age: 5 mg once daily as chewable tablets.

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.

Perennial Allergic Rhinitis With or Without Asthma
Oral

Infants 6–23 months of age: 4 mg once daily as oral granules.

Children 2–5 years of age: 4 mg once daily as chewable tablets or oral granules.

Children 6–14 years of age: 5 mg once daily as chewable tablets.

Adolescents ≥15 years of age: 10 mg once daily as film-coated tablets.

Adults

Asthma With or Without Allergic Rhinitis
Oral

10 mg once daily as film-coated tablets.

Additional dosage not needed for treatment of allergic rhinitis in patients already receiving chronic therapy for asthma.

Exercise-induced Bronchospasm
Prevention
Oral

10 mg as a film-coated tablet administered at least 2 hours before exercise.

Not indicated in those already taking the drug for another indication.

Seasonal Allergic Rhinitis With or Without Asthma
Oral

10 mg once daily as film-coated tablets.

Perennial Allergic Rhinitis With or Without Asthma
Oral

10 mg once daily as film-coated tablets.

Urticaria†
Oral

5–20 mg daily.

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild to moderate hepatic impairment. Not evaluated in patients with severe hepatic impairment or hepatitis.

Renal Impairment

No dosage adjustment required.

Geriatric Patients

No dosage adjustment required.

Cautions for Montelukast

Contraindications

  • Known hypersensitivity to montelukast or any ingredient in the formulation.

Warnings/Precautions

Warnings

Neuropsychiatric Effects

Serious neuropsychiatric effects reported with montelukast during postmarketing experience. Such reports were highly variable and included agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, dysphemia (stuttering), hallucinations, insomnia, irritability, memory impairment, obsessive-compulsive symptoms, restlessness, somnambulism, suicidal thoughts and behavior (including completed suicide), tic, and tremor in adults, adolescents, and pediatric patients with or without a previous history of psychiatric disorders. Neuropsychiatric effects occurred mostly during treatment, and resolved after the drug was discontinued; some of these effects developed or continued following discontinuance of the drug. A total of 82 cases of completed suicide associated with montelukast use identified; many of these cases reported development of concomitant neuropsychiatric symptoms prior to the event. Most reports did not contain sufficient information to determine the exact relationship between montelukast and these neuropsychiatric events. Following extensive review of postmarketing reports and analysis of available clinical data, FDA convened a panel of outside experts to reevaluate benefits and risks of montelukast and concluded that there was a need to strengthen existing warnings in the labeling for the drug, including restrictions for use in patients with allergic rhinitis. (See Allergic Rhinitis under Uses.)

Be alert to the potential for neuropsychiatric effects in patients receiving the drug. Prior to initiation of therapy, ask patients about history of psychiatric illness. Consider the risks and benefits of montelukast when deciding to prescribe therapy with the drug. Instruct patients to discontinue the drug and contact their clinician immediately if behavior or mood changes occur. If neuropsychiatric effects occur during treatment, provide patient monitoring and supportive care until symptoms resolve. Carefully evaluate the risks and benefits of reinitiating montelukast therapy in patients who develop such symptoms. (See Advice to Patients.)

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, urticaria, and, rarely, hepatic eosinophilic infiltration, reported.

Eosinophilia and Churg-Strauss Syndrome

Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, reported rarely in patients receiving leukotriene modifiers; in almost all cases, these events were associated with reduction (tapered dosage) or withdrawal of oral or high-dose inhaled corticosteroid therapy.

Be alert to the development of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy; causal relationship not established. Advise patients to report symptoms (i.e., feeling of pins and needles, numbness of extremities, flu-like symptoms, rash, sinusitis) immediately to their clinician.

Other Warnings and Precautions

Acute Asthma

Do not use for the relief of acute bronchospasm (including status asthmaticus); montelukast can be continued during acute exacerbations of asthma, but it will not provide immediate symptomatic relief.

Concomitant Corticosteroid Therapy

Do not abruptly substitute montelukast for oral or inhaled corticosteroids. Orally inhaled corticosteroid requirements may be reduced during montelukast therapy; undertake only gradual (e.g., at 2-week intervals) reduction of corticosteroid dosage.

Exercise-induced Bronchospasm

Do not use as monotherapy for prevention of exercise-induced bronchospasm; patients who experience exacerbations of asthma after exercise should continue their usual regimen of inhaled β2-adrenergic agonist for prophylaxis and have a short-acting orally inhaled β2-adrenergic agonist available for rescue.

Aspirin Sensitivity

Patients in whom asthma is precipitated by aspirin or other NSAIAs should continue to avoid aspirin and NSAIAs. Montelukast can improve airway function in asthmatic patients with aspirin sensitivity; however, the drug has not been shown to truncate the bronchoconstrictor response to aspirin or other NSAIAs.

Phenylketonuria

Montelukast chewable tablets contain aspartame (NutraSweet), which is metabolized in the GI tract to provide 0.674 mg of phenylalanine per 4-mg chewable tablet or 0.842 mg of phenylalanine per 5-mg chewable tablet.

Specific Populations

Pregnancy

Category B.

Pregnancy registry at 800-986-8999. ACOG generally recommends use of leukotriene receptor antagonists (i.e., montelukast, zafirlukast) as alternatives to a long-acting β2-agonist in pregnant women with moderate persistent asthma who are inadequately controlled with low to medium dosages of an inhaled corticosteroid. (See Asthma under Uses.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Use with caution.

Pediatric Use

Safety and efficacy for treatment of asthma in infants <12 months of age not established. Safety and efficacy for prevention of exercise-induced bronchospasm in children <6 years of age not established. Safety demonstrated in infants and children 12 months to 5 years of age with asthma; efficacy extrapolated from demonstrated efficacy in children ≥6 years of age based on similar pharmacokinetic data (systemic exposure), the similarity of the disease course, pathophysiology, and effects of the drug among these populations. Efficacy also supported by exploratory efficacy assessments from pediatric safety studies.

Safety and efficacy in infants <6 months of age with perennial allergic rhinitis not established. Safety and efficacy in infants <2 years of age with seasonal allergic rhinitis not established. Efficacy in children 2–14 years of age or 6 months to 14 years of age with seasonal or perennial allergic rhinitis, respectively, extrapolated from demonstrated efficacy in adolescents ≥15 years of age and the similarity of the disease course, pathophysiology, and effects of the drug among these populations. Safety in pediatric patients 2–14 years of age with allergic rhinitis supported by data from studies in children from this age group with asthma. Safety in infants 6–23 months of age with perennial allergic rhinitis supported by data from studies in infants with asthma and by pharmacokinetic data comparing systemic exposure in such pediatric patients with that in adults.

No effect of long-term therapy (56 weeks) on growth rate in pediatric patients (6–8 years of age) with mild asthma.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults; however, increased sensitivity in some older patients cannot be ruled out.

Hepatic Impairment

Exposure to montelukast may be increased. (See Special Populations under Pharmacokinetics and see Special Populations under Dosage and Administration.)

Common Adverse Effects

Headache, influenza, abdominal pain, cough.

Interactions for Montelukast

Metabolized by CYP3A4 and CYP2C9.

Does not inhibit CYP3A4, 2C9, 1A2, 2A6, 2C19, or 2D6. Inhibits CYP2C8 in vitro; does not inhibit CYP2C8 in vivo.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 or CYP2C9 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of montelukast).

CYP3A4 or CYP2C9 inhibitors: Potential pharmacokinetic interaction (increased plasma concentrations of montelukast).

Specific Drugs

Drug

Interaction

Comments

Benzodiazepines

No increase in adverse effects noted

Contraceptives, oral (fixed combination of ethinyl estradiol-norethindrone)

No alteration in contraceptive pharmacokinetics

Corticosteroids (prednisone, prednisolone)

No clinically important effects on corticosteroid pharmacokinetics

Decongestants

No increase in adverse effects noted

Digoxin

No alteration in digoxin pharmacokinetics

NSAIAs

No increase in adverse effects noted

Paclitaxel

No effect anticipated on paclitaxel metabolism

Phenobarbital

Decreased AUC of montelukast

Montelukast dosage adjustment not recommended; monitor for alterations in clinical response and/or adverse effects

Repaglinide

No effect anticipated on repaglinide metabolism

Rifampin

Potential for decreased montelukast concentrations

Monitor for alterations in clinical response and/or adverse effects

Rosiglitazone

No effect anticipated on rosiglitazone pharmacokinetics

Sedative-hypnotics

No increase in adverse effects noted

Terfenadine (no longer commercially available in US)

No alteration in terfenadine pharmacokinetics; no effect on QTc interval

Theophylline

No clinically important effects on theophylline pharmacokinetics at usual montelukast dosage

Decreased plasma concentrations, AUC, and half-life of theophylline at higher than recommended montelukast dosages

Thyroid hormones

No increase in adverse effects noted

Warfarin

No clinically important effects on warfarin pharmacokinetics; no alteration in PT or INR

Montelukast Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed from the GI tract; peak plasma concentrations attained within 3–4, 2–2.5, or 2 hours following oral administration in the fasted state of a single 10-mg film-coated tablet (in adults), 5-mg chewable tablet (in adults), or 4-mg chewable tablet (in children 2–5 years of age), respectively.

Oral bioavailability of the 10-mg tablet in adults is 58–66%; bioavailability of the 5-mg chewable tablet in fasting adults is 73%.

Plasma concentration profile following oral administration of montelukast 10 mg in adolescents ≥15 years of age is similar to that in young adults.

Plasma concentration profile following oral administration of 4- or 5-mg chewable tablet in children 2–5 or 6–14 years of age, respectively, is similar to the profile in adults receiving 10-mg film-coated tablet.

Systemic exposure and variability of plasma concentrations with 4-mg granule formulation in infants 6–11 months of age are greater than the exposure and variability with the 10-mg film-coated tablet in adults. Systemic exposure with 4-mg granule formulation in infants 12–23 months of age is less variable than that with the same formulation in younger children but is still greater than that with the 10-mg film-coated tablet in adults.

4-mg oral granule formulation and 4-mg chewable tablet are bioequivalent (fasting adults).

Bioequivalence of the 10-mg film-coated tablet versus two 5-mg chewable tablets not evaluated.

Onset

Improvement in asthma symptoms and/or lung function test results and decreased use of β-agonist bronchodilators are evident after the first dose.

Duration

Therapeutic effects persist for at least 24 hours.

Food

10-mg tablets: Food does not affect absorption.

5-mg chewable tablet: Food decreases extent of absorption. Bioavailability is 63% when administered with a standard meal in the morning.

4-mg oral granule formulation: High-fat meal decreases rate of absorption and peak plasma concentration; no effect on AUC. Applesauce does not appear to have a clinically important effect on the pharmacokinetics of montelukast granules.

Special Populations

In patients with mild to moderate hepatic impairment, AUC increased 41%.

Distribution

Extent

Not fully characterized.

Crosses the placenta in animals (rats, rabbits); not known whether montelukast crosses the placenta in humans.

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

99%.

Elimination

Metabolism

Extensively metabolized in the GI tract and/or liver. Several pathways have been identified, including acyl glucuronidation and oxidation catalyzed by CYP3A4 and CYP2C9.

Elimination Route

Excreted principally in feces (about 86%) via bile as unchanged drug and metabolites.

Half-life

Children 6–14 years of age: 3.4–4.2 hours.

Adults 19–48 years of age: 2.7–5.5 hours.

Special Populations

In patients with mild to moderate hepatic impairment, elimination half-life prolonged (7.4 hours). Pharmacokinetics not evaluated in patients with severe hepatic impairment or hepatitis.

In geriatric adults 65–73 years of age, elimination half-life prolonged (6.6 hours).

Stability

Storage

Oral

Granules

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Do not store opened packets or granules mixed with food, baby formula, or breast milk for future use. Administer contents within 15 minutes of opening packet.

Tablets, Chewable or Film-coated

25°C (may be exposed to 15–30°C). Protect from moisture and light.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Oral

Granules

Granules may be mixed with cold or room temperature soft food; based on stability studies, only applesauce, carrots, rice, or ice cream should be used.

Actions

  • Selective, competitive leukotriene-receptor antagonist.

  • Binds selectively and with high affinity to a group of cysteinyl leukotriene receptors (CysLT1) in airway smooth muscle and competitively inhibits the action of LTD4 (a cysteinyl leukotriene) at these receptors.

  • Modification of leukotriene activity may be used to reduce symptoms of asthma, since cysteinyl leukotrienes are especially important in the pathogenesis of asthma, causing increased mucus secretion and vascular permeability, airway edema, bronchoconstriction, and altered cellular activity associated with the inflammatory process.

  • Inhibits bronchoconstriction induced by exposure to known precipitating factors (e.g., allergens, cold and/or dry air, exercise); inhibits both the acute bronchoconstrictor response and the delayed inflammatory response to inhaled antigen.

  • May be used to reduce symptoms associated with allergic rhinitis, since cysteinyl leukotrienes are released from the nasal mucosa after allergen exposure during the early- and late-phase reactions and are associated with symptoms of allergic rhinitis.

  • Has essentially no affinity for prostanoid, cholinergic or β-adrenergic receptors.

Advice to Patients

  • Importance of patient and/or caregiver reading the manufacturer's patient information (Medication Guide) prior to initiation of therapy and with each prescription refill.

  • Importance of advising patients and their caregivers about the potential risk for serious neuropsychiatric symptoms and behavioral changes associated with use of montelukast.

  • Importance of discussing the benefits and risks of montelukast therapy with patients when deciding to prescribe or continue therapy with the drug.

  • Importance of advising patients receiving montelukast to monitor for changes in behavior or neuropsychiatric symptoms.

  • Importance of informing patients to discontinue montelukast and contact a clinician immediately if changes in behavior, new neuropsychiatric symptoms, or suicidal thoughts or behavior occur.

  • Importance of taking montelukast exactly as prescribed and not exceeding recommended frequency of use.

  • Importance of taking montelukast at regular intervals, when asymptomatic as well as during periods of worsening asthma.

  • Importance of taking montelukast at least 2 hours prior to exercise for prevention of exercise-induced bronchospasm.

  • Importance of advising patients who are receiving montelukast for chronic asthma or allergic rhinitis not to use an additional dose for the prevention of exercise-induced bronchospasm.

  • Importance of contacting clinician promptly if asthma is not well controlled; seek medical attention if short-acting, inhaled β2-adrenergic bronchodilators are needed more often than usual or if the maximum number of inhalations for a 24-hour period are exceeded.

  • Importance of not using montelukast for the relief of acute bronchospasm. Patients should be provided with and instructed in the use of a short-acting, inhaled β2-adrenergic bronchodilator as supplemental therapy for acute asthma symptoms.

  • Importance of not discontinuing or reducing the dosage of other antiasthmatic agents unless instructed to do so by the clinician.

  • In patients with known aspirin sensitivity, importance of continuing to avoid aspirin and NSAIAs.

  • Importance of informing patients with phenylketonuria that the 4- and 5-mg chewable tablets of montelukast contain phenylalanine (a component of aspartame).

  • Importance of informing clinicians immediately if symptoms of Churg-Strauss syndrome (e.g., feeling of pins and needles or numbness of extremities, flu-like symptoms, rash, sinusitis) occur.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., allergies).

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Montelukast Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Granules

4 mg (of montelukast) per packet

Singulair

Merck

Tablets, chewable

4 mg (of montelukast)

Singulair

Merck

5 mg (of montelukast)

Singulair

Merck

Tablets, film-coated

10 mg (of montelukast)

Singulair

Merck

AHFS DI Essentials™. © Copyright 2021, Selected Revisions December 21, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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